Phenylamidinothiophene derivatives and anti-inflammatory agent containing the same

ABSTRACT

A thiophene derivative containing a phenylamidino group represented by the general formula (I): ##STR1## wherein R 1  and R 2  are the same or different from each other and are hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms or an alkoxyl group having 1 to 4 carbon atoms; or a pharmacologically acceptable salt thereof. The compound is useful for the treatment of inflammatory diseases.

This application is a 371 of PCT/JP96/00372 filed on Feb. 19, 1996.

TECHNICAL FIELD

The present invention relates to novel phenylamidinothiophenederivatives and salts thereof showing an anti-inflammatory actionwithout causing the lesion of digestive organs, and an anti-inflammatoryagent containing the same.

More particularly, the present invention relates to novelphenylamidinothiophene derivatives possessing an anti-inflammatoryaction, and medicaments containing these derivatives as an effectiveingredient for the prevention and/or treatment of various inflammationreactions, and collagen disease, autoimmune disease and other variousimmune diseases in human being or animals.

BACKGROUND ART

Most of medicaments having an amidino group are circulatory agents, andothers thereof are anti-histamic agents and few thereof are centralnervous system-acting agents (Progress in Medicinal Chemistry, Vol. 30,pages 203 to 326, 1993, published by ELSEVIER CO., LTD.). As ananti-inflammatory agent, there are only naphazoline (for rhinitis) andthe like (Progress in Medicinal Chemistry, Vol. 30, page 257, 1993,published by ELSEVIER CO., LTD.). However, all of the chemicalstructures of these agents are those having an amidino group at the endof the molecule and not those having an amidino structure intermediatebetween a thiophene ring and a phenyl ring as proposed by us in thisinvention. With respect to medicaments having a thiophene ring, thosehaving anti-inflammatory action are disclosed, for example, inJP,B,3-14312 and International Publication WO 91/19708 (Tokuhyo-Hei6-501919). However, none of them have an amidino group. Thus, thecompounds proposed by us have a structure containing a phenylamidinogroup, which structure is entirely different from those ofconventionally disclosed anti-inflammatory agents.

With respect to pharmacological action of anti-inflammatory agents, itis recognized that non-steroid anti-inflammatory agents clinicallywidely used, such as aspirin and indomethacin, exert anti-inflammatoryaction through inhibition of the activity of cyclooxygenase (synthetaseof prostaglandin G/H) which is a rate-determining enzyme ofprostaglandin production. However, cyclooxygenase exists not only ininflamed regions but also in various tissues and it is recognized thatthe inhibition of cyclooxygenase activity relates to side effects ofnon-steroid anti-inflammatory agents on digestive organs or kidney.Lesion of digestive organs among the side effects is a significantfactor in limited clinical applications of non-steroid anti-inflammatoryagents.

It is an object of the present invention to provide a novel and usefulphenylamidinothiophene derivative and a salt thereof showing ananti-inflammatory action without causing lesion of digestive organs.

Another object of the present invention is to provide a medicamentcontaining the phenylamidinothiophene derivative or a pharmacologicallyacceptable salt thereof as an effective ingredient for the preventionand/or treatment of inflammatory diseases and other diseases mentionedabove without causing lesion of digestive organs.

DISCLOSURE OF THE INVENTION

The present inventors have synthesized novel compounds to solve theabove-mentioned problems and found phenylamidinothiophene derivativesrepresented by the general formula (I) mentioned below or theirpharmacologically acceptable salts which show inhibitory action on ratadjuvant arthritis and cause little lesion of digestive organs.

The present invention provides a thiophene derivative containing aphenylamidino group represented by the general formula (I): ##STR2##wherein R¹ and R² are the same or different from each other and arehydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atomsor an alkoxyl group having 1 to 4 carbon atoms; or a pharmacologicallyacceptable salt thereof.

The present invention provides the thiophene derivative containing aphenylamidino group or a pharmacologically acceptable salt thereofwherein R¹ and R² in the general formula (I) are the same or differentfrom each other and are hydrogen atom, fluorine atom, chlorine atom,bromine atom, methyl group or methoxy group.

The present invention provides 5-[N¹-(3-chlorophenyl)aminido]-2-(4-fluorophenyl)-3-(4-methylsulfonylphenyl)thiopheneor a pharmacologically acceptable salt thereof.

The present invention further provides an anti-inflammatory agentcontaining a thiophene derivative containing a phenylamidino groupmentioned above or a pharmacologically acceptable salt thereof.

The present invention still further provides use of a thiophenederivative containing a phenylamidino group mentioned above or apharmacologically acceptable salt thereof for the prevention and/ortreatment of an inflammatory disease.

Examples of the halogen atom represented by R¹ and R² in the generalformula (I) are fluorine atom, chlorine atom, bromine atom and iodineatom, among which fluorine atom, chlorine atom and bromine atom arepreferred and chlorine atom is especially preferred. Examples of thealkyl group having 1 to 4 carbon atoms are methyl group, ethyl group,n-propyl group, iso-propyl group, n-butyl group and tert-butyl group.Methyl group is especially preferred. Examples of the alkoxyl grouphaving 1 to 4 carbon atoms are methoxy group, ethoxy group, n-propoxygroup, iso-propoxy group, n-butoxy group and tert-butoxy group. Methoxygroup is especially preferred.

Combinations of kinds and positions of the substituents represented byR¹ and R² in the phenyl group contained in the phenylamidino group areappropriately selected. From the viewpoint of superior anti-inflammatoryactivity and easy production, preferred are the combinations of kindsand positions of the substituents shown in Table 1, wherein the figuresbefore the substituents indicate their positions.

                  TABLE 1                                                         ______________________________________                                               R.sup.1       R.sup.2                                                  ______________________________________                                               H             H                                                          3-Halogen H                                                                   2-Halogen H                                                                   4-Halogen H                                                                   3-Alkyl H                                                                     4-Alkyl H                                                                     3-Alkoxy H                                                                    4-Alkoxy H                                                                    2-Halogen 4-Halogen                                                           3-Halogen 4-Halogen                                                           3-Alkyl 4-Alkyl                                                               3-Alkoxy 5-Alkoxy                                                             3-Halogen 4-Alkyl                                                           ______________________________________                                    

From the viewpoint of superior anti-inflammatory activity and less sideeffect, the most preferred are 5-[N¹-(3-chlorophenyl)amidino]-2-(4-fluorophenyl)-3-(4-methylsulfonylphenyl)thiopheneand its pharmacologically acceptable salts.

The compound of the present invention includes pharmacologicallyacceptable salts of the compounds represented by the general formula(I). Generally the compounds represented by the general formula (I) arebasic and, hence, can form pharmacologically acceptable salts byreaction with many nontoxic inorganic or organic acids.

Acids usually used for formation of acid addition salts includeinorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodicacid, sulfuric acid and phosphoric acid, organic acids such asp-toluenesulfonic acid, methanesulfonic acid, oxalic acid, succinicacid, citric acid, benzoic acid and acetic acid, and the like. Amongthose, preferable pharmacologically acceptable acid addition salts areinorganic salts with hydrochloric acid or hydrobromic acid, and organicsalts with maleic acid or oxalic acid.

The novel phenylamidinothiophene derivative represented by the generalformula (I) in accordance with the present invention can be produced asshown in the following reaction formula (A): ##STR3##

In reaction formula (A), R¹ and R² are the same as defined above.

According to reaction formula (A), the phenylamidinothiophene derivative(I) can be produced by allowing a compound represented by the generalformula (III) to react with5-cyano-2-(4-fluorophenyl)-3-(4-methylsulfonylphenyl)thiophene (II)[described in International Publication WO 91/19708 (Tokuhyo-Hei6-501919)] in the presence of a Lewis acid in an appropriate organicsolvent.

The organic solvent used in the reaction of compound (II) with thecompound represented by the general formula (III) is not particularlylimited so long as the solvent does not markedly inhibit the instantreaction. However, preferred are 1,1,2,2-tetrachloroethane,N,N-dimethylformamide, dimethyl sulfoxide, and the like. As the Lewisacid, there are used aluminum chloride, boron trifluoride, tin chloride,zinc chloride, iron chloride, and the like. Aluminum chloride isespecially preferred.

With respect to the amounts of respective components in the instantreaction, the equivalent of aniline derivative (III) and that of Lewisacid are preferably 1 to 4 times, more preferably 1.5 to 3 times andpreferably 1 to 3 times, more preferably about 2 times, respectively,that of 5-cyano-2-(4-fluorophenyl)-3-(4-methylsulfonylphenyl)thiophene(II). The temperature of the instant reaction is preferably from 25° to140° C., especially from 80° to 120° C. The reaction time is preferablyfrom 1 to 10 hours, especially from 6 to 9 hours. The treatment afterthe reaction can be performed by usual treating methods, for example, byisolating and purifying the desired compound by means of arecrystallization method, a chromatography, or the like.

The compound (I) of the present invention and the pharmacologicallyacceptable salt thereof show an anti-inflammatory action without causinglesion of digestive organs. That is, they possess an anti-inflammatoryactivity and, moreover, do not inhibit the activity of cyclooxygenase invitro test, which is different from conventional non-steroidanti-inflammatory agents. Furthermore, they do not show an action ofexacerbating lesion of digestive organ in vivo test.

Therefore, the instant compounds are useful as agents for the preventionand/or treatment of various inflammation reactions, and collagendiseases, autoimmune disease and other various immune diseases in humanbeing or animals.

More specifically, the instant compounds are useful as agents for theprevention and/or treatment of inflammation and pain in joints andmuscles (e.g. rheumatoid arthritis, rheumatic spinal inflammation,osteoarthritis and gouty arthritis); inflammation of skin (e.g. solardermatitis), inflammation of eye (e.g. conjunctivitis); symptomatictherapy of inflammatory diseases in external part and fore part of eye(e.g. blepharitis, keratitis, scleritis, ureitis in fore part andpostoperative inflammation); prevention of postoperative inflammationand intraoperative or postoperative complication in operation forcataract; lung disease in which inflammation participates (e.g. asthmaand bronchitis); digestive organ disease with inflammation (e.g.aphthous ulcer, Crohn's disease, atrophic gastritis, osterogastritis,ulcerative colitis, fatty diarrhea in child, localized iletis andirritable colon syndrome); gingivitis; pain in treatment of carioustooth; headache; pain in menstrual period; inflammation after operationor injury; pain and swelling; pyrexia due to inflammation; and otherdiseases. Further, the instant compounds are expected to be useful asagents for the prevention and/or treatment of diseases of circulatoryorgan system or cerebrovascular diseases.

The compound (I) of the present invention or pharmacologicallyacceptable salt thereof can be administered orally, parenterally or byexternal application (local application) for the purpose of theabove-mentioned prevention and/or treatment.

As the formulations for medicaments, there are capsules, tablets, sugarcoated tablets, granules, inhalations, suppositories, liquids, lotions,suspensions, emulsions, ointments, cataplasms, gels, and the like.

As required, these formulations can be incorporated with excipients inorganic or inorganic solid or liquid state, auxiliary materials,stabilizing agents, wetting agents, emulsifiers, buffers, or othervarious additives.

For achievement of the desired therapeutic or preventive effect, thedaily dosage of the active ingredient is from 0.01 to 50 mg per kg bodyweight for human being. Each unit dosage form can contain 1 to 500 mg ofthe active ingredient in a state that it is mixed with a suitablecarrier for medicament. This unit dosage form can be administered 1 to 4times per day.

BEST MODE FOR CARRYING OUT THE INVENTION

The action and effect of the instant compounds are explained by means ofExperimental Examples.

The respective actions of the instant compounds on adjuvant arthritis inrats, stress ulcer in mice induced by constraint under water immersionand the activity of cyclooxygenase of sheep seminal vesicle gland wereexamined. The test methods and results thereof are shown below.

Experimental Example 1

Action on Rat Adjuvant Arthritis

Test Method

Seven-week old male Lewis rats (4 rats in one group) were injected underthe plantar skin of the right hind paw with 0.6 mg/0.1 ml of asuspension of human tubercle bacillus, killed Mycobacterium tuberculosisH37 RA in liquid paraffin, thereby inducing adjuvant arthritis. Thevolume of the adjuvant-inoculated paw (primary inflammation) wasmeasured 3 days after the inoculation of adjuvant and the volume of theadjuvant-uninoculated paw (secondary inflammation) 17 days after theinoculation of adjuvant. The swelling rate of each paw was calculatedwith respect to the volume of the paw before the inoculation ofadjuvant. Ten mg of the instant compound was suspended in 10 ml of a0.5% by weight aqueous solution of carboxymethyl cellulose and the oraladministration of the obtained suspension began on day of adjuvantinoculating and continued for 17 days in a dose of 10 mg/kg one time perday. Indomethacin was used in a dose of 1 mg/kg as a comparative drug.

Test Results

The test results are shown in Table 2 in terms of inhibition rateobtained as compared with the swelling rate of the paw in the groupgiven 0.5% by weight carboxymethyl cellulose solution. The swelling rateand inhibition rate were calculated according to the following formulae:##EQU1##

Each value is an average value for 4 rats in one group and the value inparentheses is standard error.

While in the group given indomethacin 1 mg/kg a swelling inhibition of28.8% was found for the inoculated paw and a swelling inhibition of43.6% for the uninoculated paw, there were found inhibitory actionsequal to or better than the above values in the groups given the instantcompound 10 mg/kg, especially a swelling inhibition of 31.5% for theinoculated paw and a swelling inhibition of 48.9% for uninoculated pawwith use of the compound obtained in Example 1.

                  TABLE 2                                                         ______________________________________                                        Test                                                                            compound Swelling inhibition (%)                                            (Example  Primary inflammation                                                                        Secondary inflammation                                  No.) (inoculated paw) (uninoculated paw)                                    ______________________________________                                        1         31.5 (0.91)   48.9 (3.58)                                             2 22.6 (5.24) 28.4 (2.55)                                                     3 22.1 (4.94) 32.2 (10.8)                                                     4 32.7 (7.40) 57.4 (8.54)                                                     5 23.5 (4.75) 34.7 (4.26)                                                     6 26.3 (4.37) 57.2 (5.34)                                                     7 36.1 (6.36) 48.8 (3.20)                                                     11 35.0 (10.1) 37.1 (4.42)                                                    12 18.2 (2.73) 24.9 (10.2)                                                    13 16.7 (3.25) 24.2 (5.05)                                                    17 27.4 (7.02) 44.1 (3.83)                                                    18 27.9 (3.09) 48.9 (9.69)                                                  Indomethacin                                                                            28.3 (4.10)   43.6 (9.42)                                           ______________________________________                                    

Experimental Example 2

Action on stress ulcer in mice induced by constraint under waterimmersion

Test Method

Six-week old male ddy rats (10 rats in one group) were completely fastedovernight and then loaded with constraint under water immersion for 7hours. The rats were observed under a stereoscopic microscope to examineproduction of gastric ulcer. Sum (mm) of lengths of ulcers for eachanimal was taken as ulcer index. Ten mg, 30 mg or 100 mg of the instantcompound was mixed with 0.15 ml of Tween 80 and suspended into a 0.5% byweight aqueous solution of gum arabic to give a total 10 ml of asuspension. The suspension was orally administered 15 minutes beforeloading of the constraint under water immersion. Indomethacin was usedas a comparative drug.

Test Results

The test results are shown in Table 3 in terms of an average value ofulcer indexes. In the respective groups given indomethacin 1 mg/kg and 3mg/kg, the ulcer index values were 19.0 and 28.2 and there were observedincreases in ulcer index as compared with the ulcer index, 9.0, obtainedfor the group given the solvent (which was prepared by adding 0.15 ml ofTween 80 to a 0.5% by weight aqueous solution of gum arabic so as togive a total 10 ml of a solution). In the groups given the compound ofExample 1, however, no evident difference in ulcer index was observedeven in the group given 100 mg/kg. This reveals that the instantcompound does not show such an ulcer-exacerbating action as observedwith administration of indomethacin.

                  TABLE 3                                                         ______________________________________                                        Test compound                                                                   (Example No.) Ulcer index                                                   ______________________________________                                        Solvent-given group                                                                           9.0                                                             Compound No. 1                                                                 10 mg/kg 6.5                                                                  30 mg/kg 10.8                                                                100 mg/kg 9.6                                                                 Indomethacin                                                                  1 mg/kg 19.0                                                                  3 mg/kg 28.2                                                                ______________________________________                                    

Experimental Example 3

Action on activity of cyclooxygenase of sheep seminal vesicle gland

Test Method

Two hundred and fifty μl of an enzyme solution containing each testcompound [5 mM triptophan, 200 nM hematin, 0.04% by weight Tween 20, 10units of cyclooxygenase of sheep seminal vesicle gland (made by CAYMANCO., LTD.), 2 μM [1-¹⁴ C] arachidonic acid, 0.1 M Tris-hydrochloric acidbuffer solution (pH: 8.0)], underwent a reaction at 25° C. for 6minutes. The reaction was terminated by addition of 0.5 ml of a 0.2 Mcitric acid buffer solution (pH 3.0). [1-¹⁴ C]arachidonic acid wasextracted with ethyl acetate and separated by a thin layerchromatography. The radioactivity of the resulting arachidonic acidfraction was determined with a scintillation counter and the inhibitionwas calculated.

Test Results

The test results are shown in Table 4 in terms of an average value ofinhibitions obtained from two experiments. The inhibition value wascalculated according to the following formula: ##EQU2##

Indomethacin inhibited the activity of cyclooxygenase at concentrationsof not lower than 10⁻⁸ M, which was dependent on dosage, and completelyinhibited the activity at a concentration of 10⁻⁶ M. In contrastthereto, the compound of Example 1 did not inhibit the activity ofcyclooxygenase even in 10⁻⁴ M added group.

                  TABLE 4                                                         ______________________________________                                        Test                                                                            (Example No.) Inhibition (%)                                                ______________________________________                                        Compound No. 1                                                                  10.sup.-6 M 3.4                                                               10.sup.-5 M 1.3                                                               10.sup.-4 M -2.2                                                              Indomethacin                                                                  10.sup.-8 M 15.4                                                              10.sup.-7 M 66.2                                                              10.sup.-6 M 104.9                                                           ______________________________________                                    

As described above, the compound of the present invention exerts aninhibitory effect on rat adjuvant arthritis and does not show anactivity of inhibiting the cyclooxygenase of sheep seminal vesiclegland, which is different from conventional non-steroidanti-inflammatory agents such as indomethacin and aspirin. Further, thecompound of the present invention does not show an action ofexacerbating stress ulcer in mice induced by constraint under waterimmersion, which reveals that the compound of the present invention isan anti-inflammatory agent causing less lesion of digestive organs.

The present invention will be explained more specifically by referringto Examples.

¹ H-NMR spectra were obtained using tetramethylsilane (TMS) as aninternal standard on JNM-EX 270 spectrometer (270 MHz, made by JEOLLTD.), wherein δ values are indicated in terms of ppm. The solvent usedin measuring NMR spectra was CDCl₃ unless otherwise noted. Mass spectrawere obtained on QP 1000 EX spectrometer (made by SHIMADZU CORPORATION).

EXAMPLE 1

5-Cyano-2-(4-fluorophenyl)-3-(4-methylsulfonylphenyl)thiophene (300 mg,0.837 mmol) was dissolved into 3 mm of dry 1,1,2,2-tetrachloroethane. Tothe solution was added anhydrous aluminum chloride (226 mg, 2.0equivalents) and agitated at a room temperature for an hour.m-Chloroaniline (0.14 ml, 1.5 equivalents) was added, heated up to 100°C. and agitated for 8 hours, during which an appropriate amount of theaniline was added if the amount of the aniline was reduced. The solventwas evaporated and a saturated aqueous solution of sodium hydrogencarbonate was added to the residue, followed by extraction withchloroform. The extract was washed with water, dried and concentrated.The residue was purified by a silica gel column chromatography to give apowder (356 mg) of 5-[N¹-(3-chlorophenyl)amidino]-2-(4-fluorophenyl)-3-(4-methylsulfonylphenyl)thiophene.

EXAMPLES 2 TO 18

The same procedures as in Example 1 except that substituted anilinesshown in Tables 5 to 8 were used were repeated to give desired compoundsshown in Tables 5 to 8. The yields and instrumental analysis data areshown in Tables 5 to 18.

                                      TABLE 5                                     __________________________________________________________________________    Ex.     Yield                                                                            NMR                 Mass mp                                          No. R.sup.1 R.sup.2 (%) (CDCl.sub.3, δ) (m/z) (° C.)           __________________________________________________________________________    1  3-Cl                                                                             H 90 3.08(3H, s), 4.96(2H, s), 6.89(1H, dd, J=                                                         484(M.sup.+),                                                                      188.0-                                          2.97, 7.92Hz), 6.99-7.09(4H, m), 358, 277, 188.8                              7.23-7.32(3H, m), 7.43-7.48(3H, m), 127                                       7.86(2H, d, J=8.58Hz)                                                     2 H H 95 3.07(3H, s), 4.92(2H,.s), 6.98-7.12(5H, m), 450(M.sup.+),                                              188.1-                                          7.23-7.28(2H, m), 7.34-7.47(5H, m), 357, 277, 189.4                           7.85(2H, d, J=8.58Hz) 93                                                  3 2-Cl H 93 3.08(3H, s), 4.85(2H, s), 6.99-7.07(4H, m), 484(M.sup.+),                                           115.6-                                          7.24-7.29(3H, m), 7.42-7.47(3H, m), 449, 277, 119.7                           7.51(1H, s), 7.86(2H, d, J=8.58Hz) 127                                    4 4-Cl H 70 3.23(3H, s), 6.67(2H, s), 6.88(2H, d, J= 484(M.sup.+),                                              245.2-                                          8.58Hz), 7.22(2H, t), 7.32-7.38(4H, m), 357, 277, 298.6                       7.50(2H, d, J=8.58Hz), 7.90(2H, d, J=8.58Hz), 127 (decomposed)                                                   8.00(1H, s)                                DMSO-d.sub.6                                                              5 3-F H 85 3.08(3H, s), 4.96(2H, s), 6.72-6.82(3H, m), 468(M.sup.+),                                            108.6-                                          7.02(2H, t), 7.23-7.36(3H, m), 358, 277, 112.9                                7.43-7.48(3H, m), 7.86(2H, d, J=8.58Hz) 111                             __________________________________________________________________________

                                      TABLE 6                                     __________________________________________________________________________    Ex.     Yield                                                                            NMR                Mass mp                                           No. R.sup.1 R.sup.2 (%) (CDCl.sub.3, δ) (m/z) (° C.)           __________________________________________________________________________    6  4-F                                                                              H 85 3.08(3H, s), 4.91(2H, s), 6.93-7.10(6H, m),                                                      468(M.sup.+),                                                                      212.0-                                           7.25(2H, t), 7.43-7.46(3H, m), 358, 279, 213.6                                7.86(2H, d, J=8.58Hz) 111                                                 7 4-Br H 68 3.10(3H, s), 5.66(2H, s), 6.90(2H, d, J= 530(M.sup.+),                                             249.8-                                           8.58Hz), 7.03(2H, t), 7.25-7.30.(2H, m), 357, 277, 253.0                      7.43-7.49(4H, m), 7.70(1H, s), 7.85(2H, d, 171                                J=8.58Hz)                                                                     CDCl.sub.3 +DMSO                                                          8 3-Me H 88 2.35(3H, s), 3.08(3H, s), 4.90(2H, s), 464(M.sup.+), 104.4-           6.81(2H, d, J=8.58Hz), 6.91(1H, d, J= 357, 277, 106.9                         7.59Hz), 7.01(2H, t), 7.22-7.28(3H, m), 107                                   7.43-7.46(3H, m), 7.86(2H, d, J=8.58Hz)                                   9 4-Me H 78 2.34(3H, s), 3.08(3H, s), 4.89(2H, s), 464(M.sup.+), 225.6-           6.90(2H, d, J=7.92Hz), 7.01(2H, t), 357, 277, 228.9                           7.17(2H,d , J=7.92Hz), 7.25(2H, t), 107                                       7.43-7.46(3H, m), 7.86(2H, d, J=8.58Hz)                                 __________________________________________________________________________

                                      TABLE 7                                     __________________________________________________________________________    Ex         Yield                                                                            NMR                Mass mp                                        No. R.sup.1 R.sup.2 (%) (CDCl.sub.3, δ) (m/z) (° C.)           __________________________________________________________________________    10 3-OMe                                                                             H   70 3.08(3H, s), 3.81(3H, s), 4.94(2H, s),                                                           480(M.sup.+),                                                                      200.5-                                        6.57-6.67(3H, m), 7.02(2H, t), 357, 277, 201.8                                7.23-7.30(3H, m), 7.43-7.47(3H, m), 123                                       7.86(2H, d, J=8.58Hz)                                                     11 4-OMe H 73 3.08(3H, s), 3.81(3H, s), 4.90(2H, s), 480(M.sup.+),                                                203.6-                                        6.90-7.05(6H, m), 7.25(2H, t), 357, 279, 207.5                                7.43-7.46(3H, m), 7.86(2H, d, J=8.25 123, 108                                 Hz)                                                                       12 2-F 4-F 88 3.08(3H, s), 4.96(2H, s), 6.87-6.94(2H, m), 486(M.sup.+),                                           109.0-                                        6.98-7.07(3H, m), 7.23-7.28(2H, m), 357, 277, 113.6                           7.42-7.49(3H, m), 7.86(2H, d, J=8.58Hz) 129                               13 2-Cl 4-C 1 83 3.08(3H, s), 4.88(2H, s), 6.96-7.06(3H, m), 518(M.sup.+                                          ), 174.6-                                     7.22-7.29(3H, m), 7.43-7.46(3H, m), 483, 357, 176.3                           7.51(1H, s), 7.86(2H, d, J=8.25Hz) 277, 161                               14 3-Me 4-Me 93 2.24(3H, s), 2.26(3H, s), 3.08(3H, s), 478(M.sup.+),                                              108.7-                                        4.90(2H, s), 6.74-6.80(2H, m), 7.01(2H, t), 357, 277, 111.4                                                        7.12(1H, d, J=7.59Hz),                                                   7.23-7.28(2H, m), 121                         7.43-7.46(3H, m), 7.86(2H, d, J=8.25Hz)                                 __________________________________________________________________________

                                      TABLE 8                                     __________________________________________________________________________    Ex.        Yield                                                                            NMR                 Mass mp                                       No. R.sup.1 R.sup.2 (%) (CDCl.sub.3, δ) (m/z) (° C.)           __________________________________________________________________________    15 3-OMe                                                                             5-OMe                                                                             50 3.08(3H, s), 3.79(6H, s), 4.98(2H, s),                                                            510(M.sup.+),                                                                      228.7-                                       6.18-6.23(3H, m), 7.02(2H, t), 357, 277, 231.0                                7.25(2H, t), 7.43-7.47(3H, m), 153                                            7.86(2H, d, J=8.58Hz)                                                     16 3-Cl 4-Me 85 2.35(3H, s), 3.08(3H, s), 4.92(2H, s), 498(M.sup.+),                                               209.9-                                       6.81(1H, dd), 6.99-7.05(3H, m), 357, 278, 210.8                               7.19-7.29(3H, m), 7.43-7.46(3H, m), 141, 106                                  7.86(2H, d, J=8.58Hz)                                                     17 3-Cl 4-Cl 98 3.08(3H, s), 4.97(2H, s), 6.86(1H, dd, J=2.31, 518(M.sup                                           .+), 116.1-                                  8.58Hz), 7.02(2H, t), 357, 277, 119.3                                         7.13(1H, d, J=2.31Hz), 7.25(2H, t), 161                                       7.40-7.48(4H, m), 7.86(2H, d, J=8.25Hz)                                   18 3-Cl 4-F 98 3.08(3H, s), 4.97(2H, s), 6.84-6.89(1H, m), 502(M.sup.+),                                            106.1-                                      6.99-7.17(4H, m), 7.25(2H, t), 358, 279, 110.2                                7.42-7.47(3H, m), 7.86(2H, d, J=8.58Hz) 145                             __________________________________________________________________________

Examples of formulations containing the instant compound are shownbelow.

Formulation Example 1

Into 200 ml of ethanol were dissolved 50 g of Compound No. 1 and 33 g ofpolyvinylpyrrolidone and the ethanol was distilled off under a reducedpressure. The residue was ground to a powder. To the powder were added22 g of lactose, 21 g of carboxymethyl cellulose calcium and 1 g ofmagnesium stearate. The resultant was tabletted in a usual manner togive 1,000 tablets each containing 50 mg of Compound No. 1.

Formulation Example 2

A centrifugal fluidized bed granulator (CF-360, made by Freund IndustryCo., Ltd.) was charged with 1,650 g of lactose (100 mesh, made by DMVCO., LTD.) and the lactose was coated in a usual manner by spraying5,000 ml of a solution prepared by completely dissolving 50 g ofCompound No. 1 and 310 g of hydroxypropyl methyl cellulose 2910 (HMPC2910, made by Shin-Etsu Chemical Co., Ltd.) into ethanol-methylenechloride (1:1 by volume) to give granules.

The granules were dried at 40° C. for 4 hours and treated in a usualmanner to give finished granules. The granules were mixed with 3 g ofmagnesium stearate and the resultant was charged into capsules, therebygiving 1,000 capsules each containing 50 mg of Compound No. 1.

Formulation Example 3

A centrifugal fluidized bed granulator (DF-360, Freund Industry Co.,Ltd.) was charged with 1,620 g of lactose (100 mesh, made by DMV CO.,LTD.) and the lactose was coated in a usual manner by spraying 1,000 mlof a solution prepared by completely dissolving 50 g of Compound No. 1and 310 g of hydroxypropyl methyl cellulose 2910 (HMPC 2910, made byShin-Etsu Chemical Co., Ltd.) into ethanol-methylene chloride (1:1 byvolume) to give granules. The granules were dried at 40° C. for 4 hoursand treated in a usual manner to give final granules.

The phenylamidinothiophene derivative of the present invention possessesanti-inflammatory activity and does not inhibit the activity ofcyclooxygenase and, hence, does not show an action of exacerbatinglesion of digestive organs, which are different from conventionalnon-steroid anti-inflammatory agents. Accordingly, the derivative can bean anti-inflammatory agent which is useful for prevention and treatmentof various inflammatory diseases and shows less side effect.

We claim:
 1. A thiophene derivative containing a phenylamidino grouprepresented by the general formula (I): ##STR4## wherein R¹ and R² arethe same or different from each other and are hydrogen atom, a halogenatom, an alkyl group having 1 to 4 carbon atoms or an alkoxyl grouphaving 1 to 4 carbon atoms; or a pharmacologically acceptable saltthereof.
 2. The thiophene derivative containing a phenylamidino group ora pharmacologically acceptable salt thereof according to claim 1,wherein R¹ and R² in the general formula (I) are the same or differentfrom each other and are hydrogen atom, fluorine atom, chlorine atom,bromine atom, methyl group or methoxy group.
 3. 5-[N¹-(3-chlorophenyl)aminido]-2-(4-fluorophenyl)-3-(4-methylsulfonylphenyl)thiopheneor a pharmacologically acceptable salt thereof.
 4. An anti-inflammatoryagent containing a thiophene derivative containing a phenylamidino groupset forth in any of claims 1 to 3, or a pharmacologically acceptablesalt thereof.
 5. A method of treating an inflammatory disease in apatient which comprises administering to the patient a therapeuticallyeffective amount of a thiophene derivative of formula (I) as set forthin any of claims 1 to 3, or a pharmacologically effective salt thereof.